The aim of the dissertation was to identify the systematic contributors that modify the estimated population parameters and that explain sources of variability in drug exposure (Chapter 2-4), response, and clinical outcome (Chapter 5-7). The source of measurable variability evaluated in the thesis include patient characteristics in chapter 2-3, patient behavior in chapter 4 (e.g. dosing history), biological system in chapter 5-7, and inferior clinical practice in chapter 5-7. The dissertation was predominantly non-linear mixed effect modeling and Monte Carlo simulation methods in NONMEM® and R. Our results in chapter 2-4 showed that incorporating covariate information into population PK models identified substantial systematic contributors to the variability in drug exposure for both perphenazine and escitalopram. Race and smoking status in the past week were identified as two significant covariates affecting clearance of perphenazine. CYP 2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. The measurement error associated with an incorrect or incomplete dosing history affected the population PK parameter estimation of escitalopram in the non-linear mixed effect modeling process. Furthermore, our simulation results in chapter 5-7 showed that three intervention approaches may lead to lower cardiovascular risk compared to current clinical practice strategy: 1) BP can be calibrated with respect to clinic visit times with consideration of PK/PD/dosing regimen. 2) BP-misclassification in current clinical practice is around 20~45% depends on clinic visit time. Optimal clinic visit time exists. In general, patients should avoid early morning and late afternoon visit which lead to the highest BP misclassification. 3) It is important to decrease patients BP in a timely fashion. Initiating antihypertensive treatment with the higher tolerable dose as well as setting a lower goal BP of 120 mm Hg resulted in a significantly lower cardiovascular risk. In conclusion, the dissertation identified three potential interventions to be considered in the clinical practice or antihypertensive drug labeling for better BP management: BP calibration based on clinic visit time; patients should generally have post treatment clinic visit times between 11:00 AM ~ 3:00 PM; a high dose strategy for antihypertensive drug therapy.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-01112011-114551 |
| Date | 11 January 2011 |
| Creators | Jin, Yuyan |
| Contributors | Regis R Vollmer, Robert Bies |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-01112011-114551/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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